Project Summary/Abstract Anemia of inflammation (AI) is the second most prevalent form of anemia. It is caused by chronic inflammation associated with aging and chronic diseases such as cancer and rheumatoid arthritis. While people with AI have sufficient body iron, increased sequestration due to elevated concentration of the protein hepcidin leads to insufficient circulating iron for red blood cell synthesis. AI is also exacerbated by the destruction of red blood cells (RBCs) by macrophages due to inflammation. Unfortunately, current therapies, including blood transfusion, do not reduce the elevated concentrations of hepcidin; furthermore, transfusion increases risk of excess iron, which can cause adverse effects. While experimental drugs targeting hepcidin are being developed, their long- term adverse effects are not known, warranting new non-pharmaceutical approaches. Our long-term goal is to identify dietary approaches for mitigating AI. Consumption of almonds may mitigate AI by different mechanisms; these include (i) reducing inflammation, (ii) altering the gut microbiome composition, and (iii) improving robustness of RBCs by increasing their vitamin E content, which protects them from oxidative damage. In this proposed R15 study, we will test the overall hypothesis that almond consumption will improve iron status in inflammatory states, using obese and aging mice. We chose these mouse models because both conditions are associated with inflammation, increased hepcidin, and impaired iron status markers. Our preliminary 8-week study using a mouse model of obesity provided suggestive evidence that regular almond intake reduced hepcidin and improved iron concentrations in plasma; however, a longer-duration study is needed for conclusive evidence. Our proposed study will investigate the effects of a 24-week high-fat diet with almonds (15% calories from almonds) on circulating iron concentrations in C57BL/6 mice. We hypothesize this treatment will significantly improve iron status compared to high-fat and low-fat diets. We will also investigate whether this intake of almonds can mitigate aging-related AI in C57BL/6 mice, a frequently used model in aging research. We will further probe underlying mechanisms that may influence these effects, including changes in gut microbiota composition, hepcidin concentrations, and the antioxidant system in RBCs. If our hypotheses are borne out, we will demonstrate the potential of almonds as a dietary approach to mitigating AI. Furthermore, this work would be the first to elucidate the contributions of gut microbiota and RBC antioxidant system in mitigating AI.

Project Narrative Anemia of inflammation (AI) is associated with poor immunity, impaired cognition and reduced quality of life. Especially among the elderly, AI can lead to increased recurrent falls, hospitalization, and mortality. By identifying a dietary approach for mitigating AI, this study will help to minimize its adverse health implications and improve the quality of life among at-risk populations.